title: Improvement in insulin sensitivity after human islet transplantation for type 1 diabetes.
abstract: BACKGROUND
  Islet transplantation can improve metabolic control for type 1 diabetes (T1D), an effect anticipated to improve insulin sensitivity. However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the effect of islet transplantation on insulin sensitivity in T1D using euglycemic clamps with the isotopic dilution method to distinguish between effects at the liver and skeletal muscle.
  
  
  METHODS
  Twelve T1D subjects underwent evaluation in the Clinical and Translational Research Center before and between 6 and 7 months after the transplant and were compared with normal control subjects.
  
  
  METHODS
  The intervention included intrahepatic islet transplantation according to a Clinical Islet Transplantation Consortium protocol under low-dose tacrolimus and sirolimus immunosuppression.
  
  
  METHODS
  Total body (M/Δinsulin), hepatic (1/endogenous glucose production ·basal insulin) and peripheral [(Rd - endogenous glucose production)/Δinsulin] insulin sensitivity assessed by hyperinsulinemic (1 mU·kg(-1)·min(-1)) euglycemic (∼90 mg/dL) clamps with 6,6-(2)H2-glucose tracer infusion were measured.
  
  
  RESULTS
  Glycosylated hemoglobin was reduced in the transplant recipients from 7.0% ± 0.3% to 5.6% ± 0.1% (P < .01). There were increases in total (0.11 ± 0.01 to 0.15 ± 0.02 dL/min·kg per microunit per milliliter), hepatic [2.3 ± 0.1 to 3.7 ± 0.4 × 10(2) ([milligrams per kilogram per minute](-1)·(microunits per milliliter)(-1))], and peripheral (0.08 ± 0.01 to 0.12 ± 0.02 dL/min·kg per microunit per milliliter) insulin sensitivity from before to after transplantation (P < .05 for all). All insulin sensitivity measures were less than normal in T1D before (P ≤ .05) and not different from normal after transplantation.
  
  
  CONCLUSIONS
  Islet transplantation results in improved insulin sensitivity mediated by effects at both the liver and skeletal muscle. Modern dosing of glucocorticoid-free immunosuppression with low-dose tacrolimus and sirolimus does not induce insulin resistance in this population.
authors.affiliation: MD, MS, Perelman School of Medicine at the University of Pennsylvania, 12-134 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. rickels@mail.med.upenn.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rickels
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Kong
authors.forename: Carissa
authors.initials: C
authors.lastname: Fuller
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dalton-Bakes
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.forename: Karen L
authors.initials: KL
authors.lastname: Teff
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
mesh_terms: D000328:Adult; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000601:surgery*; D005260:Female; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000378:metabolism; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use*
chemical_list: D006442:Glycated Hemoglobin; D007166:Immunosuppressive Agents; D007328:Insulin; D020123:Sirolimus; D016559:Tacrolimus